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SN-38 lipid complexes and their methods of use

a lipid complex and sn-38 technology, applied in the field of sn-38 lipid complexes, can solve the problems of insufficient repair of breakage, interference with the use of sn-38 as a therapeutic agent, and cytotoxicity in mammalian cells

Inactive Publication Date: 2003-11-20
NEOPHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] The invention provides such a composition and methods. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.

Problems solved by technology

The bound SN-38 appears to block religation of the single-strand breaks by topoisomerase-I thereby causing cytotoxicity in mammalian cells which, apparently, can not otherwise sufficiently repair the breaks.
These solubility characteristics interfere with the use of SN-38 as a therapeutic.
Moreover, the effectiveness of SN-38 after repeated administrations can be limited by the development of multi-drug resistance which not only reduces its effectiveness but also reduces the effectiveness of certain other antineoplastic therapeutics.
The general toxicity of SN-38 also limits its use therapeutically.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 2

[0040] Similar experimental conditions can be utilized with varying quantities of drug and lipid. For example, concentrations of 6 .mu.M SN-38, 6 .mu.M cardiolipin, 28 .mu.M phosphatidyl choline and 20 .mu.M cholesterol can be used by dissolving them in a suitable solvent, evaporating the solvent, and dispersing the dried lipid / drug film in a suitable aqueous solvent such as 5 ml of 7% trehalose-saline solution. Hydration of the liposomes can be facilitated by vortexing and / or sonicating the mixture. The liposomes can then be dialyzed, as desired, and the percent encapsulation of SN-38 in liposomes measured, as described above. Typically, SN-38 encapsulation will be greater than about 75% and more generally between about 85 to 95% or more as assayed by HPLC.

example 3

[0041] SN-38 can be encapsulated in liposomes by using 3 .mu.M of the drug, 15 .mu.M of dipalmitoyl phosphatidyl choline, 1 .mu.M cardiolipin, and 9 .mu.M cholesterol in a volume of 2.5 ml. The drug and lipid mixture can be evaporated under vacuum and resuspended in an equal volume of saline solution. The remainder of the process can be similar to that described above. The SN-38 encapsulation efficiency will generally be higher than 75% in this system.

example 4

[0042] In this example, liposomes containing 2 .mu.M SN-38, 2 .mu.M of phosphatidyl serine, 11 .mu.M phosphatidyl choline, 2 .mu.M cardiolipin, and 7 .mu.M cholesterol prepared by the method described in Example 1 is contemplated with greater than 75% SN-38 encapsulation efficiency.

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Abstract

The present invention is for novel compositions and methods for treating diseases caused by cellular proliferation, particularly, for treating cancer in mammals and more particularly in humans. The therapeutic compositions of the present invention include SN-38 lipid complexes in which the complexes can contain any of a variety of neutral or charged lipids and, desirably, cardiolipin. The compositions are capable of efficiently incorporating SN-38 into complexes and are capable of solubilizing relatively high concentrations of SN-38.

Description

[0001] This invention pertains to complexes of SN-38 with lipids, their methods of manufacture, and their use in the treatment of diseases, especially diseases involving eukaryotic cellular proliferation.DESCRIPTION OF THE BACKGROUND[0002] The compound known as 7-ethyl-10-hydroxycamptothecin (SN-38) and more formally as ((+)-(4S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7-]-indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, first disclosed in U.S. Pat. No. 4,473,692, is an active metabolite of irinotecan, a derivative of camptothecin. It is thought to bind to the enzyme topoisomerase I, the enzyme responsible for relieving torsional strain in DNA by inducing reversible single-strand breaks. The bound SN-38 appears to block religation of the single-strand breaks by topoisomerase-I thereby causing cytotoxicity in mammalian cells which, apparently, can not otherwise sufficiently repair the breaks.[0003] The metabolic conversion of irinotecan to SN-38 occurs primarily in the liver by ca...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K9/133A61K31/4745A61K39/395A61K47/12A61K47/22A61K47/24A61K47/26A61K47/28A61K47/42A61K47/44A61K47/48A61P35/00
CPCA61K47/48815A61K9/1272A61K47/6911A61P21/00A61P35/00A61K47/50
Inventor AHMAD, IMRANZHANG, JIA-AIRAHMAN, AQUILUR
Owner NEOPHARMA INC
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